Project Summary People with chronic kidney disease (CKD), who represent over 15% of the population of the United States, suffer a disproportionately high burden of cardiovascular disease (CVD) for reasons that are poorly understood. Inflammation represents the major pathophysiologic process common to both atherosclerosis and CKD. Recently, a novel pathway of inflammation was uncovered linking both CVD and CKD to bone marrow myeloid cells which produce a circulating signaling molecule: soluble urokinase plasminogen activator receptor (suPAR). SuPAR is released by immature myeloid cells in response to environmental exposures and CVD risk factors. In circulation, suPAR alters glomerular and tubular function, with chronic exposure leading to progressive kidney dysfunction. Pharmacologic inhibition of suPAR in experimental models prevented kidney injury. SuPAR levels also predict adverse cardiovascular outcomes independently of kidney function, and outperform well-established markers of CVD risk, such as coronary calcium, C-reactive protein, high sensitivity troponin I and B-type natriuretic peptide. These compelling data reveal the potential for suPAR not only as an excellent biomarker of risk, but also as a promising therapeutic target. The role of suPAR in CVD is however poorly understood. The overall goal of this proposal is to elucidate suPAR?s potential causal role in the progression of atherosclerosis and its link to decline in kidney function through epidemiologic insights. We will achieve this goal by leveraging three of the most significant contributions to cardiovascular science: the landmark Multi-Ethnic Study of Atherosclerosis (MESA); an NIH-funded prospective cohort in which enrollees underwent serial measurements of subclinical markers of atherosclerosis, the JUPITER trial, in which participants with high C-reactive protein levels were randomized to statin or placebo, and the UK Biobank, a data repository of over 500,000 volunteers. SuPAR levels will be measured in 5,620 participants of MESA to determine whether levels correlate with early markers of CVD and predicts their progression independently of a decline in kidney function. To assess potential causality, a gene-wide association study of suPAR levels in MESA, followed by a Mendelian randomization analysis in the UK Biobank dataset will connect genetic determinants of suPAR levels to CVD and CKD. Lastly, to establish whether suPAR is a modifiable risk factor for CVD, levels will be measured serially in participants of the JUPITER trial randomized to rosuvastatin (n=200) or placebo (n=200), and the change in suPAR will be compared between groups. Whether the benefits of statins are dependent on suPAR levels will be assessed in the MESA cohort by comparing the survival of participants started on statins across suPAR quartiles, and determining whether suPAR is a modifier of the association between statins and outcomes. The proposed research has the potential to address the unmet need of close to 50 million people with CKD in the United States alone, identifying sorely needed therapeutic targets and management strategies in a field that has long been stagnant.